The present invention relates to novel 16-xcex1 estradiol ester compounds and their use as locally active estrogens in the treatment of the symptomology of menopause.
It is well recognized that pharmacologic estrogen administration (hormone replacement therapy, HRT) can alleviate most, if not all, of the symptomology associated with the menopause. These symptoms include, but are not limited to: bone loss associated with osteoporosis; heart disease associated with changes in blood lipids and lipoproteins; hot flashes; and vaginal dyspareunia.1 However, there are risks associated with estrogen administration in HRT as well as oral contraceptive use, and include an association with endometrial cancer, breast cancer, and stroke. Although for the most part, the therapeutic benefits of HRT outweigh the risks, nevertheless, while the risks are small, they do exist.2-4 
Estrogen therapy, directly and indirectly, affects a number of organs. Some of the outcomes associated with estrogen therapy are deleterious. Consequently, where possible, symptomology which could be ameliorated by local rather than systemic administration could limit the adverse side-effects of estrogen therapy. One such syndrome that can be treated directly, caused by estrogen deprivation or estrogen antagonists, is vaginal dyspareunia. It is a common disorder which affects a large proportion of women, approximately 40% within 10 years of the onset of the menopause.5 It is and important factor in the quality of life for women so afflicted, as it is associated with a severe physical and psychological impact. It is not only painful but it can dramatically influence a women""s self image and lead to clinical depression.6 Another possible use of local estrogens includes topical administration to aging skin. The skin contains ER and it is an estrogen target organ.11-13 While topical application of estrogens to the vaginal mucosa has been used to treat vaginal dyspareunia of the menopause, these estrogens are adsorbed into the blood and result in significant blood levels of estrogens.7-10 Thus, this therapy may not be used where systemic estrogens are contraindicated.
Since topically applied estrogen is adsorbed into the blood, its purpose is defeated. A potent estrogen whose range is limited to the tissue to which it is applied would be ideal for the treatment of these disorders. Similar therapeutic agents with locally limited actions have been termed xe2x80x9csoft drugsxe2x80x9d14, compounds which have a limited region of activity due to rapid metabolic inactivation. Ester groups have been used to convey xe2x80x9csoft drugxe2x80x9d properties to biologically active molecules because hydrolytic enzymes, including esterases, are ubiquitously distributed.15 The ester containing compounds are the active agents while their hydrolysis products, the carboxylic acids, are inactive. In this manner, locally active glucocorticoids have been developed as antiinflammatory agents for the skin. These are esters of steroids substituted with a carboxylic acid group. The parent carboxylic acids do not bind to the glucocorticoid receptor and are biologically inert while their corresponding esters bind to the glucocorticoid receptor with high affinity.16,17 The esters are rapidly hydrolyzed to the parent steroidal-carboxylic acid and thus, are inactivated by the ubiquitous esterases. Consequently, they can be used as antiinflammatory agents for skin because their action is localized to the area to which they were applied, i.e., their rapid inactivation prevents systemic action.18 
Similarly, in a study designed to produce affinity chromatographic supports for the purification of the estrogen receptor (ER) it was found that carboxylic acid analogs of estradiol (E2) at C-7xcex1- and C-17xcex1 are very poor ligands if they bind at all, but the methyl esters of these same analogs have much improved affinity for the ER.19 It appears from those results that a charged carboxylic acid group in proximity to the steroid ring interferes with binding to the ER and that masking the charge by esterification reverses this interference.
It is an object of the invention to provide novel compounds and pharmaceutical compositions for use in treating the symptomology of menopause.
It is an additional object of the invention to provide prodrug forms of estrogen which may be used to provide a therapeutic effect while limiting deleterious effects which may occur with systemic administration of estrogenic steroids.
It is yet another object of the invention to provide methods for treating the symptomology of menopause, especially including vaginal dyspareunia.
It is still another object of the invention to provide topical dosage forms of the present compounds, and in particular, vaginal creams, gels and lotions for use in the treatment of certain symptoms associated with menopause, especially vaginal dyspareunia.